Wednesday, September 16, 2015

Cirrhosis of liver: Concepts, mechanism and pathophysiology

Hello everyone! 

In this really long post, I'll be discussing the pathophysiology of some of the signs, symptoms and conditions seen in chronic liver failure / alcoholic liver disease. We are going to focus on the WHY.

Let's get started ^__^

Why is gynecomastia, testicular atrophy and female pubic hair distribution seen in males with chronic liver failure?
Physiology:
- Liver metabolizes estrogens.
Pathology:
- In cirrosis, estrogen degradation is decreased, so estrogen concentration are elevated causing testicular atrophy, gynecomastia & changes in pubic hair.
- Estrogen also induces SHBG production and this further reduces the free testosterone levels.
What causes spider nevi?
- Estrogen causes spider nevi.
Mechanism?
- Cutaneous vasodilation due to estrogen.
PS: Spider nevi are also known to occur in pregnancy.

What causes palmar erythema?
- Cutaneous vasodilation due to estrogen is also the cause for palmar erythema.
PS: It's argued that NO may play a role in palmar erythema.

What causes parotid enlargement in liver cirrhosis?
A bilateral, painless hypertrophy of the parotid glands (sialadenosis) appears to be caused by a demyelinating polyneuropathy that results in abnormal sympathetic signaling, abnormal acinar protein secretion, and acinar cytoplasmic swelling.

What is fetor hepaticus?
The characteristic odor in hepatic encephalopathy. 
Biochemistry: Mercaptans are formed by the bacterial breakdown of sulphur containing amino acids (eg: methionine, cysteine) in the intestine.
Physiology: Normally, the liver demethylates these compounds and renders them odourless.
Pathology: The normal demethylating process is inhibited in liver damage which causes methyl mercaptan and dimethyldisulphide to be exhaled in breath and concreted in urine.
PS: It is also seen in portal hypertension, where portosystemic shunts open up and allow mercaptans to bypass the liver and go directly to lungs.

Why does ammonia cause hepatic encephalopathy in liver failure?
Physiology: Ammonia crosses the blood brain barrier.
Pathology: NH3 causes swelling of astrocytes and overstimulation of glutamate receptors, which induces excitotoxicity.
More detailed pathophysiology:
Astrocytes protect neurons against excitotoxicity by taking up excess ammonia and glutamate and converting it into glutamine via the enzyme glutamate synthetase.
- Hyperammonemia induces astrocyte swelling due to intracellular glutamate accumulation.
- Elevation of extracellular glutamate due to release and reduced uptake by swollen astrocytes cause overstimulation of NMDA receptors in neurons leading to excitotoxicity.
- Hyperammonemia also induces the formation of inducible nitric oxide synthase in astroglial cells, with the consequent NO formation leading to vasodilation in the brain.

A few concepts in the management of hepatic encephalopathy:
Why are non-absorbables disacharides (lactulose or lactitiol) given?
- Lactulose acidifies the gut because it is broken down into short chain fatty acids by colonic bacteria. This causes conversion of ammonia (NH3) produced by bacteria to ammonium. NH4+ is an ion and can not go back into the body through the intestine, it is thus, excreted in stools.
- Short chain fatty acids also promotes the growth of saccharolytic bacteria.
- The shorter colonic transit time due to the laxative property of lactulose also helps in the quick clearance of ammonia.

Why are non-absorbables antibiotics (neomycin, rifamyxin, metronidazol, vancomycin) used?
They kill the coliform bacteria that produce urease which convert urea to ammonia.

Why is acarbose preferred in patients with hepatic encephalopathy and type 2 diabetes mellitus?
Because it increases the ratio of sacharolytic and proteolytic bacteria.

Other medications in hepatic encephalopathy:
- Long branch aminoacids (leucine, isoleucine, valine)
- Zinc
- L- ornitine, L-aspartate
- Hypoproteic diet (aproteic if the patient is going to be cured in a few hours)
- Sodium benzoate (chelates ammonia and glutamine, renal excretion)
If the encephalopathy was caused by benzodiazepines or other sedatives)
- Flumanezil

What causes Dupuytren’s contracture in alcoholics?
The mechanism whereby alcohol intake is associated with DD is unclear. Suggestions include effects on local circulation in the palm, damage to fatty tissue provoking a fibrotic response, and changes in prostaglandin production, but none of these mechanisms has been clearly established.
MCQ: What is seen in alcoholics but not a manifestation of cirrhosis of liver.

Why do we follow effect of liver failure on coagulation by measuring PT?
Physiology: Liver synthesizes factor 2, 7, 9 and 10. (Vitamin K dependent clotting factors.)
Pathology: Liver can't make em anymore!
PS: Prothrombin time is used to assess the severity of liver disease too.. If your prothrombin time is affected, then it shows your hepatocytes are severely damaged.

What causes asterixis in liver failure?
The exact mechanism by which asterixis occurs remains unknown. A leading theory suggests interruption of the posture pathway in the rostral reticular formation and abnormal joint proprioception. The lapse of posture has been termed “negative clonus” because during tonic muscle contraction (i.e. posture) a short EMG silent period precedes the tremor. In essence, the patient struggles to maintain posture while posture control repetitively vanishes. (Source.) (You can read more here.)

Stigmata of liver disease:
Scleral icterus
Jaundice
Parotid enlargement
Leukonychia
Spider angiomata
Palmar erythema
Gynecomastia
Testicular atrophy
Paucity of axillary and pubic hair
Ascites
Caput medusase
Ankle edema
Petechiae, purpura

That's all!

I had incredible fun writing this post in such detail. I hope you enjoyed treading and understanding each concept too. Isn't medicine absolutely amazing?
Email me concepts you know that aren't included in the post, I'll add em here. Here's my email: medicowesome@gmail.com

-IkaN

18 comments:

  1. Nice collection of facts from multiple subjects. Such approach enhances and aids clinical usage/applications....Again which year are you in ??

    ReplyDelete
    Replies
    1. Thank you. I'm in my internship (or housejob) year.

      Delete
  2. Hyperammonemia induces astrocyte swelling due to intracellular glutamate accumulation.
    Elevation of extracellular glutamate due to release and reduced uptake by swollen astrocytes.. ...Sister ,I am confused with the intracellular and extracellular part ! Please be kind enough to clarify.

    ReplyDelete
    Replies
    1. The concentration of glutamate increases in the intracellular and extracellular compartment. How?

      First, extra ammonia is converted into glutamine and stored inside the astrocytes. But there is a limit to how much a poor little astrocyte can take in. It swells, swells until it can take no more glutamate inside it (Reduced glutamate uptake).

      It also starts letting go a few glutamate into the extracellular environment which it can't convert into glutamine. Conversion requires the enzyme (Glutamate synthetase), and if the enzyme is busy, and the cell is full of glutamate, it releases a few molecules (Glutamate release).

      Hope that clears it for you, brother! :)

      Delete
    2. Thank you sis,,,,,Keep smiling, keep smiling and we'll see what tomorrow brings.
      Keep smiling, keep smiling and be thankful for the little things.
      Cause we won't be around forever, so come on all let's join in together.
      Back to back you know it's up to you,It's amazing what a single friendly smile could do.
      Never under estimate yourself or any others,
      Cause deep down we're connected like sisters and brothers.. { bars &melody}

      Delete
  3. Hey can u plz help me in short term n long term regulation of blood pressure?

    ReplyDelete
  4. Great post! can you please answer that MCQ you put? What is seen in alcoholics but not a manifestation of cirrhosis of liver? Thanks!

    ReplyDelete
    Replies
    1. The answer is dupuytren's contracture! :)

      Delete
    2. I don't know if thats true. Although it has been seen that dupytren's is more common in someone with alcoholic cirrhosis, there is no definitive proof just yet. It's been seen in both types of cirrhosis. Ofcourse if you have a source to this, i would love to see it!

      But i believe uptodate mentions this and explicitly states that this has not been proven just yet, its just more common in alcoholics.

      Delete
  5. Also you might want to add:
    What causes Anemia in cirrhosis:
    1) Transcobalamine 2 is produced by the liver which binds to Vitamin B12. Deficiency of the transporter can yield a megaloblastic anemia.
    2) Hypersplenism secondary to portal HTN leads to normocytic anemia.

    What can cause Thrombocytopenia due to cirrhosis?
    2 Proposed mechanism
    1) Hypersplenism (disputed)
    2) Thrombopoetin is produced by the liver.

    ReplyDelete
    Replies
    1. Oh I never thought of these things. Interesting! Thanks for sharing it with us. I'll incude it in the main post soon!

      Delete
  6. Your answers have been very helpful thank you �� also I would like to know what is the cause for asterixis(Flapping tremors) ?

    ReplyDelete
  7. Thanks alot dear...good effort to make these complex things into simple form..

    ReplyDelete

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